Cough is the most common symptom for which patients seek medical advice from primary health care providers. Current antitussive therapies are minimally effective and have side effects that limit their utility. In the United States alone, over 2 billion dollars are spent annually on over the counter cough remedies with questionable efficacy, potential toxicity, and abuse potential, and billions more are spent annually in sick days and doctor's visits. Cough is the primary mechanism of transmission of airborne infections, including all forms of influenza, tuberculosis and Bordetella pertussis, the gram negative bacterium causing whooping cough. As such, cough represents a major public health issue that is poorly treated with currently existing therapies. Currently existing cough medications include dextromethorphan and codeine. People suffering from coughing, sneezing, rhinorrhea, and/or nasal obstruction generally take throat lozenges, cough syrups, and cough drops containing these medications for symptomatic relief. While such medications presently exist, there is room for significant improvement in the composition, efficacy, and adverse effect profiles of these medications.
Other medications currently in the market contain a combination of antitussives, for example one or more expectorants, mucolytics, decongestants, antipyretics, analgesics, or combinations thereof. While such combinations may be acceptable to some patients, others may have restrictions due to allergies or other incompatibilities with certain ingredients. Furthermore, many of these medications contain sugar or alcohol. Many patients suffering from cough would prefer medications that do not include sugar or alcohol. Moreover, the commonly used antitussive agent dextromethorphan has a potential for abuse and because of its lack of potency and side effects profile, has demonstrated limited efficacy in clinical trials. Therefore, there is a need for medications that treat/prevent coughing, sneezing, rhinorrhea, and/or nasal obstruction with fewer side effects, less drug abuse potential, free of sugar and added alcohol. This need is highlighted by the broad repercussions of acute cough on patient quality of life, school and work productivity, and public health resources. The available treatment options are limited and lack clinically proven efficacy and reliability to support their use. As such, there is an unmet need to develop new antitussive therapeutics. Specifically, new antitussive therapeutics that can provide rapid relief or suppression of cough with minimal or no side effects are particularly desirable.
Antitussive drugs may act peripherally to inhibit cough by suppressing the responsiveness of one or more vagal sensory receptors that produce cough (Spina et al., Handb Exp Pharmacol. 2009; (187): 155-186; Undem and Carr, Chest, 2010, 137(1): 177-184. Antitussive drugs may also act within the central nervous system at the level of the brain stem, where the basic neural circuitry responsible for cough is located (Bolser et al., Respir Physiol Neurobiol., 2006; 152(3): 255-265; Canning, Pulm Pharmacol Ther. 2009; 22(2): 75-81). Specifically, centrally-acting antitussives are thought to inhibit cough by interfering with the central modulation of afferent signals from the periphery, thereby decreasing the sensitivity of the cough center located within the medulla to incoming stimuli. As an N-Methyl-d-aspartate (NMDA) glutamate receptor antagonist, dextromethorphan is thought to be a centrally-acting antitussive.
A recent model of the basic cough circuitry suggests that the eupneic respiratory pattern and the cough motor pattern are produced by essentially the same neural components. Although this pattern generator normally controls the breathing, its behavior is modified to produce cough by excitatory inputs from medullary second order interneurons mediating pulmonary C-fiber and cough receptor-afferent information. Centrally acting antitussive drugs may act at any level within this system. For example, these drugs could suppress the responsiveness of components of the central pathway by transmitting vagal sensory information (second-order interneurons) and/or can have more complex effects on the motor pattern generator for cough (Bolser et al., Respir Physiol Neurobiol., 2006; 152(3): 255-265; Canning, Pulm Pharmacol Ther. 2009; 22(2): 75-81).
Memantine (MMT), (3,5-dimethyltricyclo[3.3.1.13,7]decan-1-amine or 3,5-dimethyladamantan-1-amine) is the first in a novel class of Alzheimer's disease medications acting on the glutamatergic system by blocking only open NMDA receptor ion channels. Unlike dextromethorphan and some other drugs with significant abuse potential, it does not interact with the enigmatic sigma receptor, partially explaining its lack of hallucinogenic effects. MMT has been used for some time in the elderly as a disease modifying agent and to improve the symptoms of moderate to severe Alzheimer's disease. Recent animal studies suggest that memantine may also be useful for pain treatment and protection against nerve cell damage (neuroprotection). MMT is currently approved for the treatment of moderate to severe Alzheimer's disease, and clinical experience has been remarkable for efficacy and minimal side effects and lack of abuse liability in this population.